High affinity small molecule binding to the normally folded structural ensemble of an aggregation-prone protein stabilizes its native state, lowering the population of misfolded, misassembly competent states that lead to aggregates. Crafting small molecules that bind the normally folded conformational of an aggregation-prone protein is a promising strategy to treat amyloid diseases.  Here, we focus on transthyretin (TTR) amyloidosis: demonstrating that preferential ligand stabilization of the native tetrameric state of TTR over the dissociative transition state dramatically raises thekinetic barrier of dissociation in turn slowing and sometimes halting the process of TTR amyloid fibril formation. Clinical analysis has shown that Tafamidis, a small molecule kinetic stabilizer of TTR, halts the progression of Familial Amyloid Polyneuropathy. Tafamidis may also ameliorate the cardiomyopathies associated with amyloidogenesis of wild-type TTR or selected mutants. This seminar will also focus on the intimate cooperation between academia and industry that led to this first-in-class drug.

Vyndaqel: A transthyretin kinetic stabilizer that halts peripheral neuropathy is a first-in-class drug for a human amyloid disease

243rd National Meeting (2012)

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